Heterosexual transmission accounts for the majority of new cases of HIV-1 infection each year. Recent[unreadable] reports from the World Health Organization estimate that a total of 38 million people are now infected with[unreadable] HIV-1 worldwide; 90% of whom live in developing countries. Nearly 50% of all infected individuals were[unreadable] women. The increased incidence of HIV-1 infection in women, particularly those of childbearing age,[unreadable] underscores the urgent need for effective preventative and therapeutic options that are safe, affordable and[unreadable] culturally accepted. In the absence of an effective preventative vaccine, topical microbicides may offer a[unreadable] practical alternative to block HIV-1 transmission at the site of entry. We seek funds to determine whether the[unreadable] process of RNA interference (RNAi) can be harnessed to prevent the cervico-vaginal transmission of HIV-1[unreadable] and thereby emerge as a novel microbicidal strategy. This work will be conducted by investigators at Rhode[unreadable] Island Hospital, Brown University (B. Ramratnam) and Harvard-NEPRC (K. Mansfield). RNAi refers to the[unreadable] sequence-specific degradation of RNA that follows the cellular introduction of homologous, short interfering[unreadable] (si) RNA. We hypothesize that RNAi can be specifically targeted to the mucosal surfaces and decrease the[unreadable] expression of host factors that mediate HIV-1/SIV mucosal transmission. For these proof-of-principle studies,[unreadable] we will target the CCR5 chemokine receptor in macaques. We will pursue three specific aims over the 12-[unreadable] month period. 1: To characterize the tissue penetrance of liposomal and nanaocapsule formulated siRNA[unreadable] following direct mucosal application. 2: To quantify the kinetics and durability of mucosal CCR5 knockdown[unreadable] following single and serial mucosal applications of siRNA. 3. To conduct virus challenge experiments in[unreadable] siRNA treated animals. At the end of the granting period, we will have defined the HIV-1 microbicidal[unreadable] potential of siRNA.